SGLT2 inhibitor effective but risky in type 1 patients

Action Points

Note that this randomized trial of canagliflozin found an elevated risk of DKA in treatment arms at various doses, but no DKA events in those receiving placebo.

Note that the SGLT-2 inhibitor class has been associated with DKA in other studies as well.

Type 1 diabetes patients taking canagliflozin (Invokana) off-label were at a higher risk of of ketoacidosis than were those on placebo in a randomized trial.

The drug, an SGLT-2 inhibitor for patients with type 2 diabetes, was associated with a serious case of diabetic ketoacidosis (DKA) in five of 117 patients on 100 mg/day of the drug and in seven of 117 on 300 mg/day in an 18-week trial funded by Janssen, which markets the drug.

None of the 117 patients in the placebo group had DKA, reported Anne Peters, MD, at the University of Southern California, and colleagues in Diabetes Care.

After 18 weeks, the incidence of any ketone-related adverse event was 5.1% (n=6) in the 100-mg group and 9.4% (n=11) in the 300-mg group.

"Because of the potentially life-threatening nature of DKA in patients with type 1 diabetes, further development of SGLT2 inhibitor therapy as a treatment for type 1 diabetes should proceed with caution," concluded the authors.

Among those who had serious adverse events, blood glucose levels varied from 9.4 to more than 44.4 mmol/L (170 to >800 mg/dL). There were no significant differences at baseline between the treatment and control groups that predicted a ketone related adverse event.

The FDA issued a warning last May that canagliflozin and other drugs in the class -- dapagliflozin (Farxiga) and empagliflozin (Jardiance) -- were associated with ketoacidosis.

Efficacy results from the trial were reported last October in Diabetes Care, showing that canagliflozin reduced HbA1c levels and body weight in type 1 diabetes patients. The current analysis took a closer look at the adverse events.

All patients in the study were adults with type 1 diabetes for at least 1 year and an HbA1c level of 7.0-9.0% at screening. They were on a stable insulin regimen and had a BMI of 21-35 at baseline. Those with a history of type 2 diabetes, DKA, a recent severe hypoglycemic incident, or cardiovascular problems were excluded from the study.

Before the trial began, patients with an HbA1c level of ≤8.0% were recommended to reduce their basal insulin dose by 20%; those with a level of >8.0% were recommended to increase their insulin dose by 10%.

Most patients in all three groups had adverse events. In the canagliflozin arms, most were related to the mechanism of SGLT2 inhibition, such as urinary tract infections. One patient in the 100-mg group and two in the 300-mg group discontinued the drug because of adverse events; no patients on placebo did. The incidence of serious adverse events were 7.7% and 6.8% for the 100- and 300-mg groups, respectively.

Most of the ketone-related adverse events happened within one month of beginning treatment. Three of twelve patients with DKA had a history of ketoacidosis. The authors added that future trials of type 1 diabetes patients on an SGLT2 inhibitor should routinely monitor blood and urine ketones, use lower doses, interrupt treatment during illness or surgery, discontinue treatment if ketone levels remain high, and provide guidelines for patients about when to contact a doctor.

A limitation of the study was that the researchers knew very little about the risk of DKA when the study began. In addition, patients weren't told to record details about their treatment regimen, so it's unknown what details could've affected the risk of DKA.

"Patients, treating physicians, and emergency care providers must be made aware of the potential risks of DKA with SGLT2 inhibitor therapy," wrote Peters and colleagues. "Patients taking SGLT2 inhibitors and their physicians should closely monitor serum ketones when patients are ill, have reduced insulin and/or food intake, or experience any circumstance that is known to be associated with an increased risk of DKA."

The American Association of Clinical Endocrinologists held a consensus conference last year on this issue and determined that “the risk-benefit ratio overwhelmingly favors continued use of SGLT2 [inhibitors] with no changes in current recommendations.”

The study was funded by Janssen, which markets canagliflozin. The journal paper was written with support from an employee of MedErgy HealthGroup.

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